Position emission tomography (PET) offers the possibility of measuring noninvasively regional myocardial blood flow, substrate fluxes and biochemical reaction rates in the human heart. A multitude of positron emitting tracers is available. Studies with PET and radiotracers in animals and in humans have been encouraging and appear to have direct clinical impact. However, PET studies have remained largely qualitative. The metabolism of radiotracers and the fate of the label in myocardium as reflected by rates of tracer tissue uptake and clearance needs to be defined and its relationship to the physiologic process as for example blood flow, oxygen, glucose and fatty acid metabolism and TCA cycle activity firmly established so that tracer kinetic models can be validated or newly developed. Through these tracer kinetic models operational equations are derived which then quantify regional functional processes in the human heart in ml or mmol/min/gram myocardium. The research seeks to continue development and/or validation of PET measurement techniques, specifically of glucose, fatty acid, oxygen and TCA cycle metabolism and blood flow. It also seeks to clarify mechanisms and pathophysiology of PET observations in human myocracial ischemia. The proposed studies will largely be performed in acute or chronic dog experiments, including biochemical assays of myocardial tissue and blood, tissue histology and autoradiography. Once vailidated in animals, these techniques will then be tested in human subjects. The proposed research forms the basis for developing PET into a tool for studying the human heart's normal and abnormal physiology. With this tool then, mechanisms of disease can be examined and the severity of the disease process determined. This will directly impact detection and treatment of human cardiac disease, design of new therapeutic strategies and monitoring effects of therapy.